Tommaso Bizzarro

A meta-analytic review of the Bethesda System for Reporting Thyroid Cytopathology: Has the rate of malignancy in indeterminate lesions been underestimated?

The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) provides a 6‐tier diagnostic framework using uniform criteria in reports of thyroid aspirates. One of the major advantages of this framework is its association with defined risks of malignancy, allowing standardized management algorithms for each diagnosis. The objective of the current meta‐analysis was to demonstrate the feasibility of using TBSRTC among specimens in the atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) and follicular neoplasm or suspicious for neoplasm (FN/SFN) categories. The authors also evaluated both the morphologic features and the risk of malignancy in the presence of Hurthle cells.

Young investigator challenge: The morphologic analysis of noninvasive follicular thyroid neoplasm with papillary‐like nuclear features on liquid‐based cytology: Some insights into their identification

Noninvasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP) represents a challenge for the diagnosis and management of thyroid carcinoma. Some authors have proposed histological criteria that are able to distinguish NIFTPs from invasive follicular variant of papillary thyroid carcinoma (I‐FVPTC). Hence, NIFTPs may have repercussions in the diagnostic categories on fine‐needle aspiration. In the current study, the authors evaluated the criteria for NIFTPs on liquid‐based cytology samples.

The impact of FNAC in the management of salivary gland lesions: Institutional experiences leading to a risk-based classification scheme

Fine‐needle aspiration cytology (FNAC) has proven its value as an essential step in the diagnosis of salivary gland lesions. Although the majority of salivary gland lesions, especially those that are common and benign, can be diagnosed with ease on FNAC, limited cellularity and morphologic lesion heterogeneity can pose diagnostic challenges and lead to false‐positive and false‐negative diagnoses. This study presents the institutional experience of FNAC of salivary gland lesions from 2 academic centers.

Morphological parameters able to predict BRAF(V600E) -mutated malignancies on thyroid fine-needle aspiration cytology: Our institutional experience

The BRAFV600E mutation is the most common diagnostic/prognostic marker in papillary thyroid carcinoma (PTC). Its evaluation is typically performed with DNA‐based techniques; nonetheless, a few articles have recently proposed the morphological prediction of BRAFV600E in histological PTCs. We investigated this morphological parameter in our cytological series.

Comparison between cytospin and liquid-based cytology in urine specimens classified according to the Paris System for Reporting Urinary Cytology.

The current study compared ThinPrep urinary cytology and conventional cytospin urinary cytology in the diagnosis of bladder cancer, applying the Paris System for Reporting Urinary Cytology.

The Role of CD56 in Thyroid Fine Needle Aspiration Cytology: A Pilot Study Performed on Liquid Based Cytology

Background Fine needle aspiration Cytology (FNAC) fulfills a reliable role in the evaluation of thyroid lesions. Although the majority of nodules are quite easily diagnosed as benign or malignant, 30% of them represent an indeterminate category whereby the application of ancillary techniques (i.e. immunocytochemistry-ICC and molecular testing) has been encouraged. The search for a specific immunomarker of malignancy sheds light on a huge number of ICC stains although none of them attempt to yield 100% conclusive results. Our aim was to define in a pilot study on thyroid FNAC whether CD56 might be a valid marker also in comparison with HBME-1 and Galectin-3. Materials and Methods Inasmuch as this is the largest pilot study using only liquid based cytology (LBC), we selected all the cases only in the categories of benign nodules (BN) and positive for malignancy (PM) for validation purposes. Eighty-five consecutive (including 50 PM and 35 BN) out of 950 thyroid FNACs had surgical follow-up. The ICC panel (HBME-1, Galectin-3 and CD56) was carried out on LBC and histology. Results All BNs and PMs were histological confirmed. CD56 was negative in 96% of the PM while 68.5% of the BNs showed cytoplasmic positivity for this marker, with an overall high sensitivity (96%) but lower specificity (69%). In specific, our 96% of the PMs did not show any follicular cell with CD56 expression. Different ICC combinations were evaluated showing that the panel made up of CD56 plus HBME-1 and Galectin-3 had the highest sensitivity (98%) and specificity (86%). Conclusions Our pilot study suggests that CD56 may be a good marker for ruling out PTC and its variants. The low specificity suggests that an immunopanel including also HBME-1 and Galectin-3 could obtain the highest diagnostic accuracy in thyroid lesions. Our results suggest that CD56 may be a feasible additional marker for identifying malignancies also in the FNs and SMs.

The diagnostic and prognostic role of liquid-based cytology: are we ready to monitor therapy and resistance?

Here, we evaluate the diagnostic and prognostic role of liquid-based cytology (LBC) in different body lesions, including thyroid, lung, effusions and malignant breast lesions. LBC has gained consensus after being applied to both non-gynecologic and fine-needle aspiration cytology. Although some remain sceptical regarding the diagnostic efficacy of LBC, mainly when used alone, in recent years, good results have been obtained as long as it showed a high diagnostic accuracy. Here, we discuss the additional possibility of storing material for the application of ancillary techniques (immunocytochemistry–molecular analysis) with several diagnostic and prognostic advantages, which may pave the way for the challenging evaluation of both monitoring responses to treatment and resistance to targeted therapies in thyroid, lung, breast carcinoma or malignant effusions. Furthermore, it provides the use of several molecular spots as specific targets for personalized therapy.

Uncommon BRAF mutations in the follicular variant of thyroid papillary carcinoma: New insights

Mutational analysis is reshaping the practice of fine‐needle aspiration cytology for the diagnosis of thyroid nodules. The v‐Raf murine sarcoma viral oncogene homolog B1 (BRAF) valine (V) to glutamic acid (E) substitution at codon 600 (BRAFV600E) is the most effective diagnostic/prognostic marker and is used mainly for papillary thyroid carcinomas (PTCs). Although BRAFV600E represents 95% of all BRAF mutations, uncommon BRAF mutations have been identified in thyroid carcinomas. For the current study, the authors evaluated morphologic (plump pink cells and sickle‐shaped nuclei) anti‐BRAFV600E antibody (VE1) immunocytochemical and molecular findings of BRAF mutations in PTCs and in the follicular variant of PTC (FVPC).

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): Implications for the risk of malignancy (ROM) in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC)

The introduction of noninvasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP) affects the risk of malignancy (ROM) mostly in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) categories. In this multi‐institutional, retrospective study, the authors investigated variations in the impact of an NIFTP diagnosis on the associated ROM for each TBSRTC category with an emphasis on the influence of pathologist and institutional diagnostic thresholds on the ROM.

Is morphology alone able to predict BRAF-mutated malignancies on thyroid FNAC?

We read with interest the original investigation by Virk et al. concerning morphological features that may predict BRAF V600E mutation in papillary thyroid carcinomas, reporting some conflicting results but also highlighting our points of view and our case study on this challenging topic [1]. Recently, prospective and retrospective studies have shown that the presence of this mutation is very frequent in the classical variant of papillary thyroid carcinoma (PTC). Furthermore, this mutation is associated with unfavorable outcome [2]. Although the gold standard for assessing the status of the BRAF gene is based upon DNA analysis, this may not represent the most cost-effective option. As molecular analysis of DNA is not universally available several studies have explored whether specific morphological features might predict the presence of a BRAF mutation [3]. Virk et al. suggest that BRAF-mutated PTC show distinctive morphological features including the presence of “plump cells,” large polygonal tumor cells with a height of the cell less than twice the width, and squamoid metaplasia, consisting of cells with homogeneous, eosinophilic, moderate to abundant cytoplasm, and nuclear features of PTC. The authors found that 29 out of 50 (72 %) PTC had these “plump cells” as well as a V600E BRAF mutation, whereas they occurred in only 28 % of wild-type PTC [1]. This is in keeping with the data from Finkelstein et al. who found identical morphological features in 65 % of BRAF-mutated PTC [3]. These two papers did not quantify the presence of “plump cells,” even though it may be relevant to report if this feature is valid only when numerous “plump cells” can be seen, or maintains its association with the BRAF-mutated status when just a few isolated “plump cells” are present. The awareness of this histological finding lead us to look for their presence in cytology samples of thyroid lesions diagnosed as positive for malignancy (PM). All our cytology cases had been processed using a liquid-based (LBC) method with reliable results. We re-analyzed all our 72 PM cytology cases collected in the period 2012–2013. We excluded all the cytology cases diagnosed as malignant with oxyphilic and tall cell variant features that may induce a misdiagnosis. Our intention was to (1) identify “plump cells” and (2) tentatively quantify their presence into (a) diffuse (more than 20 % “plump cells”) and (b) limited (less than 20 %). The results of this study are partially in keeping with the Virk et al. data. Of our 72 cytology PM cases 47 (65 %) had a BRAF mutation. While Virk et al. described these “plump cells” in 72 % of their BRAFmutated cases we found them in all mutated cases (Fig. 1). The presence of “plump cells” was diffuse in 41 (87 %) cases whereas in the remaining six cases this was limited. Of the 25 BRAF wild-type cases, five E. D. Rossi (*) : T. Bizzarro :G. Fadda : L. M. Larocca Division of Anatomic Pathology and Histology, Università Cattolica del Sacro Cuore, “Agostino Gemelli” School of Medicine, Largo Francesco Vito, 1, 00168 Rome, Italy e-mail: esther.rossi@rm.unicatt.it